What is Rett Syndrome?
 

Rett Syndrome (RTT) is a severe neurological disorder primarily affecting females, caused by mutations in the Methyl-CpG binding protein 2 (MECP2) gene located on the X chromosome. Symptoms typically begin to manifest between 6 and 18 months of age. Following a brief period of normal development after birth, patients undergo a developmental regression, characterized by loss of acquired language and hand skills, development of stereotypic hand movements, gait abnormalities, breathing irregularities (apnea, hyperventilation), scoliosis, anxiety, and sleep disturbances. The incidence of RTT is approximately 1 in 10,000 to 1 in 15,000 live female births.
 

Pathogenesis
 

The core pathogenesis of Rett Syndrome is closely linked to loss-of-function mutations in the MECP2 gene. This gene encodes Methyl-CpG binding protein 2 (MeCP2), a crucial epigenetic regulator that dynamically controls the expression of thousands of downstream genes by recognizing DNA methylation marks. On one hand, MeCP2 recruits co-repressor complexes, such as histone deacetylases, to condense chromatin structure and inhibit gene transcription. On the other hand, it can also directly promote gene expression by interacting with transcriptional activators, as seen in its regulation of Brain-Derived Neurotrophic Factor (BDNF). During neurodevelopment, MeCP2 maintains precise gene expression programs, acting as a central "master switch" for neuronal maturation, dendritic spine morphology, synaptic plasticity, and the excitatory/inhibitory balance of neural circuits.
 

Mutations in the MECP2 gene impair MeCP2 protein function. The consequent loss of transcriptional regulation leads to genome-wide expression dysregulation, damaging synaptic structure and function, and particularly affecting GABAergic inhibitory neurons. This ultimately results in dysfunction of critical neural networks in the brain, manifesting as typical symptoms like developmental regression, motor dysfunction, epilepsy, and autonomic respiratory dysregulation. In Rett Syndrome, the most common MECP2 gene mutations are concentrated at specific "hotspot" sites, such as nonsense mutations p.Arg168X, p.Arg255X, p.Arg270X, p.Arg294X, and missense mutations like p.Thr158Met (T158M), p.Arg106Trp (R106W), p.Arg133Cys (R133C), and p.Arg306Cys (R306C).
 

In addition to MECP2, mutations in genes like CDKL5 and FOXG1 can cause atypical Rett Syndrome. CDKL5, a kinase, regulates MeCP2 activity through phosphorylation, indirectly affecting neuronal function. The transcription factor FOXG1, involved in forebrain development, shares pathway intersections with MeCP2. Mutations in these genes interfere with common downstream networks, leading to neurodevelopmental phenotypes similar to RTT.
 

 

(Image: MECP2 Dysfunction in Rett Syndrome: Molecular Mechanisms, Multisystem Pathology, and Emerging Therapeutic Strategies)

 

Gene Therapy
 

AAV Gene Therapy: In March 2025, the Guangzhou Women and Children's Medical Center completed the first gene therapy for Rett Syndrome in central-southern China. This treatment uses AAV vectors to deliver a functional MECP2 gene directly to affected neurons in the patient's brain, aiming to repair neural cell function and alleviate neurodevelopmental symptoms.

A-to-I RNA Editing: This approach uses A-to-I RNA editing technology to convert the R270X nonsense termination mutation into a tryptophan codon, potentially restoring MECP2 function. Experimental results in mouse models have shown promising efficacy without significant behavioral differences.

Alternative Gene Therapy: This strategy aims to improve RTT symptoms by overexpressing a transgenic neurotrophic factor (TF). Researchers packaged the TF coding sequence into AAV-PHP.eB vectors, known for their ability to effectively cross the rodent blood-brain barrier (BBB), under the control of an astrocyte-specific promoter. Results indicated that low-dose AAV-TF treatment significantly improved motor behavior in MECP2 knockout mice.

 

Mouse Models
 

MECP2 KO Mice: Complete knockout of the MECP2 gene, modeling the pathological features of Rett Syndrome. These mice exhibit neurological symptoms similar to RTT, such as motor dysfunction, respiratory abnormalities, and premature death.

MECP2 T158A Mice: Carry the p.Thr158Ala mutation, which specifically disrupts the DNA-binding ability of the MeCP2 protein, used to study the effects of this functional loss.

MECP2 R306C Mice: Carry the p.Arg306Cys mutation, which primarily affects the MeCP2 protein's ability to recruit transcriptional repression complexes, used to elucidate the role of transcriptional dysregulation.

Viaat-Mecp2 Mice: Feature specific knockout of the MECP2 gene in GABAergic neurons, used to study the role of these neurons in Rett Syndrome.

 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models, enabling editing at virtually any target gene locus. Complete homozygous gene-edited mouse models can be prepared directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various RTT mouse models according to client needs, such as MECP2 KO mice, MECP2 T158A mice, MECP2 R306C mice, and Viaat-Mecp2 mice. We welcome inquiries!

 

References:

[1] Merck Manual Professional Edition. Rett Syndrome. Pediatrics: Congenital Neurologic Anomalies.

[2] Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018 Feb;8(2):170216. doi: 10.1098/rsob.170216. PMID: 29445033; PMCID: PMC5830535.

[3] Wu Hao, Zhong Min. Research Progress on Molecular Genetics and Treatment of Rett Syndrome. Modern Medicine & Health, 2024, (11): 1945-1949. DOI: 10.3969/j.issn.1009-5519.2024.11.030.

[4] Liyanage VR, Rastegar M. Rett syndrome and MeCP2. Neuromolecular Med. 2014 Jun;16(2):231-64. doi: 10.1007/s12017-014-8295-9. Epub 2014 Mar 11. PMID: 24615633; PMCID: PMC5798978.

[5] Lu S, Chen Y, Wang Z. Advances in the pathogenesis of Rett syndrome using cell models. Animal Model Exp Med. 2022 Dec;5(6):532-541. doi: 10.1002/ame2.12236. Epub 2022 Jul 4. PMID: 35785421; PMCID: PMC9773312.[6] Choi G, Lee S, Yoo S, Do JT. MECP2 Dysfunction in Rett Syndrome: Molecular Mechanisms, Multisystem Pathology, and Emerging Therapeutic Strategies. Int J Mol Sci. 2025 Aug 26;26(17):8277. doi: 10.3390/ijms26178277. PMID: 40943197; PMCID: PMC12428351.

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